Publications by authors named "Kensuke Daida"

Objective: Variants in PRKN and PINK1 are the leading cause of early-onset autosomal recessive Parkinson's disease, yet many cases remain genetically unresolved. We previously identified a 7 megabases complex structural variant in a pair of monozygotic twins using Oxford Nanopore Technologies (ONT) long-read sequencing. This study aims to determine if ONT long-read sequencing can detect a second variant in other unresolved early-onset Parkinson's disease (EOPD) cases with 1 heterozygous PRKN or PINK1 variant.

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Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations.

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Article Synopsis
  • Copy Number Variations (CNVs) are crucial in understanding complex diseases and vary across different populations, necessitating large sample studies for accurate analysis.
  • The CNV-Finder pipeline utilizes deep learning, specifically Long Short-Term Memory (LSTM) networks, to streamline the identification of CNVs in specific genomic areas, making subsequent analyses like genome sequencing more efficient.
  • The tool has been validated with data from various cohorts, focusing on genes related to neurological diseases, and includes an interactive web application for researchers to visualize and refine their findings based on model predictions.
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Background: Mutations within the genes and are the leading cause of early onset autosomal recessive Parkinson's disease (PD). However, the genetic cause of most early-onset PD (EOPD) cases still remains unresolved. Long-read sequencing has successfully identified many pathogenic structural variants that cause disease, but this technology has not been widely applied to PD.

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Parkinson's disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants.

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A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson's disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson's Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.

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Background: biallelic pathogenic variants are the most common cause of autosomal recessive early-onset Parkinson's disease (PD). However, the variants responsible for suspected PD individuals are not always identified with standard genetic testing.

Objectives: Identify the genetic cause in two siblings with a -PD phenotype using long-read sequencing (LRS).

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Parkinson's disease (PD) significantly impacts millions of individuals worldwide. Although our understanding of the genetic foundations of PD has advanced, a substantial portion of the genetic variation contributing to disease risk remains unknown. Current PD genetic studies have primarily focused on one form of genetic variation, single nucleotide variants (SNVs), while other important forms of genetic variation, such as structural variants (SVs), are mostly ignored due to the complexity of detecting these variants with traditional sequencing methods.

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Background: Chronic constipation is a common digestive complication of Parkinson's disease (PD).

Objectives: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD.

Methods: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period.

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Article Synopsis
  • Mutations in the PRKN gene are the leading cause of young onset Parkinson's disease and are found in a genetically fragile region, suggesting potential undiscovered complex structural variants.* -
  • The study utilized various genetic sequencing methods, including long-read sequencing, to investigate twins with early-onset dystonia-parkinsonism, uncovering a significant 7 Mb inversion in the PRKN gene.* -
  • Findings from the UK-Biobank and AMP-PD datasets identified several potentially harmful inversions, demonstrating the effectiveness of long-read sequencing in discovering complex genetic variants linked to Parkinson's disease.*
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Article Synopsis
  • Mutations in specific regions of the human genome are a major cause of young onset and autosomal recessive Parkinson's disease (PD), with complex structural variants often remaining undetected.
  • The research aimed to uncover these complex structural variants using advanced long-read sequencing techniques, particularly focusing on cases involving monozygotic twins with dystonia-parkinsonism.
  • The findings revealed a significant 7Mb inversion and a heterozygous exon 3 deletion, marking the first report of such a large inversion, highlighting the potential of long-read sequencing in diagnosing complex genetic issues in young-onset PD cases.
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Long-read sequencing technologies substantially overcome the limitations of short-reads but have not been considered as a feasible replacement for population-scale projects, being a combination of too expensive, not scalable enough or too error-prone. Here we develop an efficient and scalable wet lab and computational protocol, Napu, for Oxford Nanopore Technologies long-read sequencing that seeks to address those limitations. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the National Institutes of Health Center for Alzheimer's and Related Dementias.

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Background: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations.

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Article Synopsis
  • The study focuses on understanding genetic factors contributing to Parkinson's disease (PD) within African and African admixed populations to advance precision medicine.
  • A genome-wide assessment involving nearly 200,000 individuals identified a significant risk factor linked to the gene at locus rs3115534-G, with a strong correlation to PD onset and a mechanism related to gene expression rather than coding mutations.
  • The findings suggest this genetic variant is uniquely prevalent among African ancestries, highlighting the importance of diverse populations in researching complex diseases like PD.
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Long-read sequencing technologies substantially overcome the limitations of short-reads but to date have not been considered as feasible replacement at scale due to a combination of being too expensive, not scalable enough, or too error-prone. Here, we develop an efficient and scalable wet lab and computational protocol for Oxford Nanopore Technologies (ONT) long-read sequencing that seeks to provide a genuine alternative to short-reads for large-scale genomics projects. We applied our protocol to cell lines and brain tissue samples as part of a pilot project for the NIH Center for Alzheimer's and Related Dementias (CARD).

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Article Synopsis
  • The α-Synuclein V15A variant has been linked to Parkinson's disease in two Caucasian families, but its significance was previously unclear.
  • Researchers conducted a comprehensive analysis of the variant's effects on phospholipid binding and protein aggregation in cells, discovering it to be rare and potentially pathogenic.
  • V15A showed stronger amplification of α-Syn fibrils compared to wild-type and had a lowered affinity for phospholipids, suggesting it could contribute to Parkinson's disease development.
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  • * Brain imaging indicated that the patient had progressive brain calcification, initially linked to her treatment for a craniopharyngioma 14 years prior.
  • * Although parkinsonism has not been previously reported as a symptom of radiation-induced calcification, the extent of calcification affecting the brain's white matter likely contributed to her motor issues.
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  • A study was conducted on 2,527 Parkinson's disease (PD) patients to explore the effects of parkin RBR E3 ubiquitin protein ligase (PRKN) variants, enrolling 2,322 patients, including those with familial and sporadic PD.
  • Out of 242 patients with identified PRKN variants, 13 were newly discovered, and patients were categorized based on whether they had one or two mutated alleles.
  • Those with two mutated alleles experienced earlier onset of PD symptoms and exhibited more severe disease progression over 15 years compared to those with only one mutated allele, indicating a correlation between the number of mutations and symptom severity.
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Individuals with hereditary spastic paraplegia (HSP) are known to present with a variety of symptoms, including intellectual disability, cognitive decline, parkinsonism, and epilepsy. We report here our experience of treating a family with consanguinity, including three patients with HSP-related symptoms. We performed whole-exome sequencing and identified a novel pathogenic nonsense variant, c.

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Introduction: To identify and investigate patients with Parkinson's disease (PD) harboring VPS35 variants in Japan.

Methods: Using targeted gene panel screening, we analyzed 393 familial, 294 young-onset, and 52 late-onset sporadic PD patients derived from the Juntendo PD DNA bank, and obtained clinical information from the medical records on each patient in whom we found VPS35 p.D620N variants.

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The present report documents a patient harboring an alpha-synuclein p.A53T variant from a family presenting with autosomal dominant inheritance, including four patients clinically diagnosed with Parkinson's disease (PD) and two with dementia. The alpha-synuclein p.

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